dbSNP rs587776441: TRNV:p.Asp15Asn (chrM-1644-G-A) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

Variant has been reported in ClinVar as Likely pathogenic (★★★).

Frequency

Mitomap GenBank:

Absent

Consequence

TRNV
missense

Scores

Mitotip

Uncertain

Clinical Significance

Likely pathogenic reviewed by expert panel P:3O:1

Leigh-Syndrome-/-HCM-/-MELAS,Adult-Leigh-Syndrome

Conservation

PhyloP100: 0.980

Variant links:

Genes affected

TRNV (HGNC:7500): (mitochondrially encoded tRNA valine)

TRNV links:

RNR2 (HGNC:7471): (mitochondrially encoded 16S RNA) Enables G protein-coupled receptor binding activity; protein self-association; and receptor antagonist activity. Involved in several processes, including leukocyte chemotaxis; negative regulation of cell death; and negative regulation of neuroinflammatory response. Located in several cellular components, including mitochondrion; perinuclear region of cytoplasm; and sperm midpiece. [provided by Alliance of Genome Resources, Apr 2022]

RNR2 links:

RNR1 (HGNC:7470): (mitochondrially encoded 12S RNA) Enables DNA binding activity and DNA-binding transcription factor binding activity. Involved in several processes, including osteoblast proliferation; regulation of carbohydrate utilization; and regulation of phosphate metabolic process. Located in extracellular space; mitochondrion; and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

RNR1 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

No frequency data in Mitomap. Probably very rare.

PP5

Variant M-1644-G-A is Pathogenic according to our data. Variant chrM-1644-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 689846.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank
TRNV	unassigned_transcript_4786	c.43G>A	p.Asp15Asn	missense_variant	Exon 1 of 1
RNR2	unassigned_transcript_4787	n.-27G>A		upstream_gene_variant
RNR1	unassigned_transcript_4785	n.*43G>A		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt

Frequencies

GnomAD4 exome

Cov.:

We have no GnomAD4 genomes data on this position. Probably position not covered by the project.

Gnomad homoplasmic

AF:

0.0

AC:

AN:

56431

Gnomad heteroplasmic

AF:

0.000018

AC:

AN:

56431

Mitomap

Leigh-Syndrome-/-HCM-/-MELAS,Adult-Leigh-Syndrome

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

MELAS syndrome

Pathogenic:2Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jul 12, 2019

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NC_012920.1:m.1644G>A variant in MT-TV gene is interpreted to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: PS3, PS5, PP3 -

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mitochondrial disease

Pathogenic:1

Dec 10, 2021

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The m.1644G>A variant in MT-TV was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID: 32906214). This variant has been reported in 7 individuals with primary mitochondrial disease with variable features including cardiac (hypertrophic cardiomyopathy, LBBB); neurologic (neurodegeneration/dementia, stroke-like episodes, recurrent encephalopathy, epilepsy, ataxia, dystonia, Parkinsonism, mood disorder/disturbances, fatigue, muscle weakness, exercise intolerance, neuropathy, cognitive impairment, developmental regression); audiologic (bilateral sensorineural hearing loss); renal (cystic renal disease); GI (severe GI dysmotility, cachexia); and endocrine (diabetes) concerns as well as lab abnormalities (elevated blood and CSF lactate, elevated CK), and brain imaging abnormalities (atrophy, basal ganglia lesions, MRS lactate peak); with heteroplasmy levels in multiple tissues ranging from 85% to homoplasmy (PS4; PMIDs: 15320572, 23847141, 18314141, 21986556, 24691472). This variant heteroplasmy level segregated with severity in 2 family members from 1 family (PP1; PMID: 15320572). This variant is located at the same position as another variant associated with mitochondrial disease, m.1644G>T (PM5_supporting). This variant is absent in the GenBank data set and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant impacts the function of this tRNA, as does HmtVar with a score of 1 (PP3). Cybrid studies supported the functional impact of this variant (PS3_supporting; PMID: 24691472). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4, PS3_supporting, PM2_supporting, PM5_supporting, PP1, PP3. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction